Lung cancer is the most common cause of cancer-related death worldwide and intrinsic therapeutic resistance of non small cell lung cancer (NSCLC) cells remains a major challenge in improving the effectiveness of cancer therapy. Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile/ xenobiotic detoxification enzymes and drug efflux proteins and confers cytoprotection against oxidative stress and apoptosis in normal cells. Kelch-like ECH-associated protein (Keap1) negatively regulates Nrf2 activity by targeting it for proteasomal degradation. We recently reported that biallelic inactivation of Keap1 results in constitutive activation of Nrf2 function in NSCLC. Preliminary studies indicate that constitutive activation of Nrf2 in lung cancer cells increases activity of central metabolic pathways, promotes in vivo tumor growth and contributes to chemoresistance. Thus, we hypothesize that the gain of Nrf2 function resulting from the loss of Keap1 activity promotes tumorigenesis and confers therapeutic resistance and wild type Keap1 functions as a tumor suppressor by inhibiting the activity of Nrf2. Specific Aim 1: To test the hypothesis that the gain of Nrf2 function promotes lung tumorigenesis (in the presence of an oncogenic signal). Specific Aim 2: To test the hypothesis that restoring wild type Keap1 function in NSCLC cells with high Nrf2 levels attenuates Nrf2 activity and suppresses tumor growth. Specific Aim 3: To test the hypothesis that the gain of Nrf2 function in lung cancer cells increases glucose flux through pentose phosphate pathway and Tricarboxylic acid cycle essential for promoting tumor growth. Specific Aim: To test the hypothesis that blocking the activity of Nrf2-dependent phosphate pathway enzymes (Glucose-6 phosphate dehydrogenase and Transketolase) in NSCLC cells with gain of Nrf2 function inhibits tumor growth and attenuates chemoresistance. These aims will help in understanding the regulation of lung tumorigenesis by a novel pathway and develop a strategy for targeting this pathway to circumvent therapeutic resistance. PUBLIC HEALTH RELEVANCE: The studies proposed in this project have potential for developing new means to inhibit tumor progression and chemoresistance. Successful completion of this project will develop a new therapeutic strategy for lung cancer treatment.